Fragile X (fra X) syndrome, the most common heritable cause of neuropsychiatric disability, is caused by mutations of the FMRI gene. Our previous research showed that individuals with fra X manifest a characteristic set of maladaptive behaviors, and a particular profile of cognitive strengths and weaknesses. Initial studies of genetic and environmental correlates of the fra X neuropsychiatric profile further suggest (1) an association between FMRI activation and specific domains of cognitive function and, (2) that the profile and magnitude of environmental influences on neurobehavioral outcome may be altered in children with fra X compared to non-fra X controls. Particular brain regions also are morphologically abnormal in persons with fra X; of particular note are findings of aberrant volume, and indirect evidence of abnormal function of the hippocampus and amygdala. Combined with data indicating that hyperarousal, social anxiety and visual-spatial deficits are key components of the fra X phenotype, and pilot data indicating abnormal cortisol secretion in affected individuals, these findings suggest dysfunction of limbic-hypothalamic-pituitary-adrenal (HPA) systems in this condition. The overarching goal of our newly proposed studies is to expand our knowledge of the association of specific genetic, environmental, neuroendocrine and neuroanatomical factors with neuropsychiatric outcome in children with fra X. To accomplish this goal, three specific aims are identified. In the first aim, we will enhance our understanding of the relation between specific genetic and environmental factors and cognitive and behavioral outcome in children with fra X. In the second aim, we will measure the function and reactivity of the HPA axis in this same population. These two aims will be accomplished with in-home evaluation of 150 children with fra X and 150 unaffected siblings. In the third aim, we will utilize structural and functional brain imaging in individuals with fra X to identify the specific neurofunctional systems underlying cognitive and behavioral abnormalities. This last aim will be achieved using structural and functional MRI, and FDG-PET studies. The information gained from this work will contribute to our understanding of the complex interplay among gene state, brain function, hormonal milieu and environmental influences in fra X. The proposed studies are especially designed to provide practical information regarding neurobiological, hormonal and environmental factors that may be directly amenable to intervention. Study of this important single gene condition also will contribute to our fundamental knowledge of linkages among gene, environment, brain, and behavior in children.